Machine learning reveals sex-biased platelet-associated molecular signatures in systemic lupus erythematosus

Autoimmune diseases (ADs) demonstrate a higher prevalence in women than men. Systemic Lupus Erythematosus (SLE) stands out among multiple ADs as an extreme case of the imbalanced sex ratio observed at disease onset, predominantly affecting females. This discrepancy can be ascribed to genetics, hormonal influences, environmental triggers, and more. Despite numerous studies aiming to uncover the sex differences in SLE, comprehensive bioinformatics integration for understanding its biological heterogeneity remains largely unexplored.

Transcriptomic data of 338 individuals (175 normal and 163 SLE) from the six SLE studies (GSE154851, GSE20864, GSE99967, GSE39088, GSE72754, and GSE81622) from the Gene Expression Omnibus were analyzed to uncover sex-specific candidate genes using differential gene expression analysis. Machine learning algorithms selected the candidate genes, and their performance was evaluated using receiver operating characteristic curves. Analyses were done by ADEx, GEO2R, and scRNA-seq.

72 enriched terms are shared between the female subgroup and the overall dataset, but none are shared between the male subgroup and the overall dataset. We identified differential expression of platelet glycoprotein VI (GP6) in male SLE, but not in the females, with GP6 predominantly expressed in platelets. Moreover, the correlation between GP6 and pre-T cell antigen receptor alpha (PTCRA) was significantly more pronounced in male SLE patients (r = 0.7004, p = 0.0053) compared to females (r = 0.5741, p < 0.0001). Additionally, GP6 and PTCRA were positively associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in male SLE patients, but not in females.

There is a sex-based bias in SLE. GP6 marks a PTCRA-expressing platelet subset that is differentially altered in male SLE compared with controls, but not in female SLE, indicating a sex-dependent platelet molecular phenotype. The differential GP6 expression on PTCRA-expressing platelets between male and female SLE patients may contribute to differences in their clinical manifestations.